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    Bernal P, Civantos C, Filloux A, Llamas MAet al.,

    Type VI secretion in the plant growth promoting rhizobacteria Pseudomonas putida

    , FEMS Microbiology Congress 2015

    BackgroundBacterial type VI secretion systems (T6SSs) are recently discovered nanomachines used to inject effectors into prokaryotic or eukaryotic cells. Therefore, T6SSs are involved in both inter-bacterial competition and bacterial pathogenesis.ObjectivesThe aim is the study of the T6SS of Pseudomonas putida a soil bacterium with the capacity to colonise the root of crop plants. The colonisation by this bacterium provides growth advantages to the plant and, importantly, protection against plant pathogens. This makes P. putida a relevant biocontrol agent. Since T6SS is mainly used by environmental bacteria for interbacterial competition, one might speculate that T6SSs play a relevant role in the biocontrol properties of P. putida. Methods• in silico analysis of P. putida KT2440 genome • Competition assays to determine H1-T6SS activity and for the identification of H1-T6SS targets.• Regulatory studies: qRT-PCR, transcriptional fusionsConclusionsThe in silico analysis has revealed the existence of three putative T6SSs (H1, H2, and H3). The clusters contain the genes encoding the conserved core components and some accessories, including regulatory proteins and toxins-immunity pairs. Additional T6SS-related genes are found scattered on the chromosome.By competition assays we have determined that H1-T6SS is active and that mutants in H1-T6SS structural components lack the ability to kill model prey strains. Moreover, the system can be used to kill serious phytopathogens such as Pseudomonas syringae in in vitro assays. Interestingly, the H1-T6SS is induced in stationary phase and controlled by the global regulators RetS and GacS-GacA, and by two alternative sigma factors, RpoS and RpoN.

    Dominguez-Huttinger E, Boon NJ, Clarke TB, Tanaka RJet al.,

    Mathematical modelling of colonization, invasive infection and treatment of Streptococcus pneumoniae

    , Frontiers in Physiology, ISSN: 1664-042X

    Streptococcus pneumoniae (Sp) is a commensal bacterium that normally resides on the upper airway epithelium without causing infection. However, factors such as co-infection with influenzavirus can impair the complex Sp-host interactions and the subsequent development of manylife-threatening infectious and inflammatory diseases, including pneumonia, meningitis or evensepsis. With the increased threat of Sp infection due to emergence of new antibiotic resistant Sp strains, there is an urgent need for better treatment strategies that effectively prevent progression of disease triggered by Sp infection, minimizing the use of antibiotics. The complexity of the host-pathogen interactions has left the full understanding of underlying mechanisms of Sp-triggered pathogenesis as a challenge, despite its critical importance in the identification of effective treatments. To achieve a systems-level and quantitative understandingof the complex and dynamically-changing host-Sp interactions, here we developed a mechanisticmathematical model describing dynamic interplays between Sp, immune cells, and epithelial tissues, where the host-pathogen interactions initiate. The model serves as a mathematical framework that coherently explains various in vitro and in vivo studies, to which the model parameters were fitted. Our model simulations reproduced the robust homeostatic Sp-host interaction, as well asthree qualitatively different pathogenic behaviours: immunological scarring, invasive infectionand their combination. Parameter sensitivity and bifurcation analyses of the model identified the processes that are responsible for qualitative transitions from healthy to such pathologicalbehaviours. Our model also predicted that the onset of invasive infection occurs within less than 2 days from transient Sp challenges. This prediction provides arguments in favour of the use of vaccinations, since adaptive immune responses cannot be developed de novo in such a short time. We further designe

    Liew N, Mazon Maya M, Wierzbicki C, Hollinshead M, Dillon M, Thornton C, Ellison A, Cable J, Fisher M, Mostowy Set al.,

    Chytrid fungus infection in zebrafish demonstrates that the pathogen can parasitise non-amphibian vertebrate hosts

    , Nature Communications, ISSN: 2041-1723
    Mostowy S,

    Chytrid fungus infection in zebrafish demonstrates that the pathogen can parasitise non-amphibian vertebrate hosts

    , Nature Communications
    Pallett MA, Crepin VF, Serafini N, Habibzay M, Kotik O, Sanchez-Garrido J, Di Santo J, Shenoy AR, Berger CN, Frankel GMet al.,

    Bacterial Virulence Factor Inhibits Caspase-4/11 Activation in IntestinalEpithelial Cells

    , Mucosal Immunology, ISSN: 1935-3456

    The human pathogen enteropathogenic Escherichia coli (EPEC), as well as the mouse pathogen Citrobacter rodentium, colonize the gut mucosa via attaching and effacing lesion formation and cause diarrheal diseases. EPEC and C. rodentium type III secretion system (T3SS) effectors repress innate immune responses and infiltration of immune cells. Inflammatory caspases such as caspase'1 and caspase'4/11 are crucial mediators of host defense and inflammation in the gut via their ability to process cytokines such as IL'1β and IL'18. Here we report that the effector NleF binds the catalytic domain of caspase'4 and inhibits its proteolytic activity. Following infection of intestinal epithelial cells (IECs) EPEC inhibited caspase'4 and IL'18 processing in an NleF'dependent manner. Depletion of caspase'4 in IECs prevented the secretion of mature IL'18 in response to infection with EPEC@nleF. NleF'dependent inhibition of caspase'11 in colons of mice prevented IL'18 secretion and neutrophil influx at early stages of C. rodentium infection. Neither wild'type C. rodentium nor C. rodentium@nleF triggered neutrophil infiltration or IL'18 secretion in Cas11 or Casp1/11 deficient mice. Thus, IECs play a key role in modulating early innate immune responses in the gut via a caspase'4/11 ' IL'18 axis, which is targeted by virulence factors encoded by enteric pathogens

    Wilkinson RJ, Esmail H, Lesosky M, Lai RP, Wilkinson KA, Graham CM, Coussens AK, Oni T, Warwick J, Said-Hartley Q, Koegenelburg CF, Walzl G, Flynn JL, young DB, Barry CE, O'Garra Aet al.,

    [18F]-FDG PET/CT characterisation of progressive HIV-associated tuberculosis

    , Nature Medicine, ISSN: 1546-170X

    Tuberculosis is classically divided into states of latent infection and active disease. Usingcombined positron emission and computed tomography in 35 asymptomatic, antiretroviraltherapy naïve, HIV-1 infected adults with latent tuberculosis, we identified ten individualswith pulmonary abnormalities suggestive of subclinical, active disease who weresignificantly more likely to progress to clinical disease. Our findings challenge theconventional two-state paradigm and may aid future identification of biomarkers predictiveof progression.

    Ale A, Crepin VF, Collins JW, Constantinou N, Habibzay M, Babtie AC, Frankel G, Stumpf MPet al., 2017,

    Model of Host-Pathogen Interaction Dynamics Links In Vivo Optical Imaging and Immune Responses.

    , Infect Immun, Vol: 85

    Tracking disease progression in vivo is essential for the development of treatments against bacterial infection. Optical imaging has become a central tool for in vivo tracking of bacterial population development and therapeutic response. For a precise understanding of in vivo imaging results in terms of disease mechanisms derived from detailed postmortem observations, however, a link between the two is needed. Here, we develop a model that provides that link for the investigation of Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli (EPEC). We connect in vivo disease progression of C57BL/6 mice infected with bioluminescent bacteria, imaged using optical tomography and X-ray computed tomography, to postmortem measurements of colonic immune cell infiltration. We use the model to explore changes to both the host immune response and the bacteria and to evaluate the response to antibiotic treatment. The developed model serves as a novel tool for the identification and development of new therapeutic interventions.

    Bernal P, Allsopp LP, Filloux A, Llamas MAet al., 2017,

    The Pseudomonas putida T6SS is a plant warden against phytopathogens.

    , ISME J

    Bacterial type VI secretion systems (T6SSs) are molecular weapons designed to deliver toxic effectors into prey cells. These nanomachines have an important role in inter-bacterial competition and provide advantages to T6SS active strains in polymicrobial environments. Here we analyze the genome of the biocontrol agent Pseudomonas putida KT2440 and identify three T6SS gene clusters (K1-, K2- and K3-T6SS). Besides, 10 T6SS effector-immunity pairs were found, including putative nucleases and pore-forming colicins. We show that the K1-T6SS is a potent antibacterial device, which secretes a toxic Rhs-type effector Tke2. Remarkably, P. putida eradicates a broad range of bacteria in a K1-T6SS-dependent manner, including resilient phytopathogens, which demonstrates that the T6SS is instrumental to empower P. putida to fight against competitors. Furthermore, we observed a drastically reduced necrosis on the leaves of Nicotiana benthamiana during co-infection with P. putida and Xanthomonas campestris. Such protection is dependent on the activity of the P. putida T6SS. Many routes have been explored to develop biocontrol agents capable of manipulating the microbial composition of the rhizosphere and phyllosphere. Here we unveil a novel mechanism for plant biocontrol, which needs to be considered for the selection of plant wardens whose mission is to prevent phytopathogen infections.The ISME Journal advance online publication, 3 January 2017; doi:10.1038/ismej.2016.169.

    Bosi E, Fondi M, Orlandini V, Perrin E, Maida I, de Pascale D, Tutino ML, Parrilli E, Lo Giudice A, Filloux A, Fani Ret al., 2017,

    The pangenome of (Antarctic) Pseudoalteromonas bacteria: evolutionary and functional insights.

    , BMC Genomics, Vol: 18

    BACKGROUND: Pseudoalteromonas is a genus of ubiquitous marine bacteria used as model organisms to study the biological mechanisms involved in the adaptation to cold conditions. A remarkable feature shared by these bacteria is their ability to produce secondary metabolites with a strong antimicrobial and antitumor activity. Despite their biotechnological relevance, representatives of this genus are still lacking (with few exceptions) an extensive genomic characterization, including features involved in the evolution of secondary metabolites production. Indeed, biotechnological applications would greatly benefit from such analysis. RESULTS: Here, we analyzed the genomes of 38 strains belonging to different Pseudoalteromonas species and isolated from diverse ecological niches, including extreme ones (i.e. Antarctica). These sequences were used to reconstruct the largest Pseudoalteromonas pangenome computed so far, including also the two main groups of Pseudoalteromonas strains (pigmented and not pigmented strains). The downstream analyses were conducted to describe the genomic diversity, both at genus and group levels. This allowed highlighting a remarkable genomic heterogeneity, even for closely related strains. We drafted all the main evolutionary steps that led to the current structure and gene content of Pseudoalteromonas representatives. These, most likely, included an extensive genome reduction and a strong contribution of Horizontal Gene Transfer (HGT), which affected biotechnologically relevant gene sets and occurred in a strain-specific fashion. Furthermore, this study also identified the genomic determinants related to some of the most interesting features of the Pseudoalteromonas representatives, such as the production of secondary metabolites, the adaptation to cold temperatures and the resistance to abiotic compounds. CONCLUSIONS: This study poses the bases for a comprehensive understanding of the evolutionary trajectories followed in time by this peculiar

    Brown RL, Clarke TB, 2017,

    The regulation of host defences to infection by the microbiota

    , IMMUNOLOGY, Vol: 150, Pages: 1-6, ISSN: 0019-2805

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